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dc.contributor.authorMontes-Grajales, Diana
dc.contributor.authorBernardes, Gonçalo JL
dc.contributor.authorOlivero-Verbel, Jesus
dc.date.accessioned2016-01-06T17:10:53Z
dc.date.available2016-01-06T17:10:53Z
dc.date.issued2016-02-15
dc.identifier.citationD. Montes-Grajales et al. Chemical Research in Toxicology (2015). volume 29, issue 2: pp. 150-161. doi:10.1021/acs.chemrestox.5b00342
dc.identifier.issn0893-228X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/253117
dc.description.abstractHumans are exposed to a huge amount of environmental pollutants called endocrine disrupting chemicals (EDCs). These molecules interfere with the homeostasis of the body, usually through mimicking natural hormones leading to activation or blocking of their receptors. Many of these compounds have been associated with a broad range of diseases including the development or increased susceptibility to breast cancer, the most prevalent cancer in women worldwide, according to the World Health Organization. Thus, this article presents a virtual high-throughput screening (vHTS) to evaluate the affinity of proteins related to breast cancer, such as ESR1, ERBB2, PGR, BCRA1, and SHBG, among others, with EDCs from urban sources. A blind docking strategy was employed to screen each protein-ligand pair in triplicate in AutoDock Vina 2.0, using the computed binding affinities as ranking criteria. The three-dimensional structures were previously obtained from EDCs DataBank and Protein Data Bank, prepared and optimized by SYBYL X-2.0. Some of the chemicals that exhibited the best affinity scores for breast cancer proteins in each category were 1,3,7,8-tetrachlorodibenzo-p-dioxin, bisphenol A derivatives, perfluorooctanesulfonic acid, and benzo(a)pyrene, for catalase, several proteins, sex hormone-binding globulin, and cytochrome P450 1A2, respectively. An experimental validation of this approach was performed with a complex that gave a moderate binding affinity in silico, the sex hormone binding globulin (SHBG), and bisphenol A (BPA) complex. The protein was obtained using DNA recombinant technology and the physical interaction with BPA assessed through spectroscopic techniques. BPA binds on the recombinant SHBG, and this results in an increase of its α helix content. In short, this work shows the potential of several EDCs to bind breast cancer associated proteins as a tool to prioritize compounds to perform in vitro analysis to benefit the regulation or exposure prevention by the general population.
dc.description.sponsorshipThis work was supported by Colciencias (567-2012 to D.M-G., 1107-519-29058, 1107-459- 21616), the University of Cartagena (0342010) and the EPSRC. G.J.L.B. is a Royal Society University Research Fellow.
dc.languageEnglish
dc.language.isoen
dc.publisherAmerican Chemical Society (ACS)
dc.subjectEndocrine disrupting chemical
dc.subjectBPA
dc.subjectbreast cancer
dc.subjectcircular dichroism
dc.subjecthighthroughput virtual screening
dc.titleUrban Endocrine Disruptors Targeting Breast Cancer Proteins.
dc.typeArticle
dc.description.versionThis is the author accepted manuscript. The final version is available from ACS via http://dx.doi.org/10.1021/acs.chemrestox.5b00342
prism.endingPage161
prism.publicationDate2015
prism.publicationNameChem Res Toxicol
prism.startingPage150
prism.volume29
rioxxterms.versionofrecord10.1021/acs.chemrestox.5b00342
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2015-12-23
dc.contributor.orcidLopes Bernardes, Goncalo [0000-0001-6594-8917]
dc.identifier.eissn1520-5010
rioxxterms.typeJournal Article/Review
pubs.funder-project-idEngineering and Physical Sciences Research Council (EP/M003647/1)
pubs.funder-project-idEuropean Commission (EC) (852985)
cam.issuedOnline2016-01-11
rioxxterms.freetoread.startdate2016-12-23


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